tbuckley/cabot-search huggingface dataset:
Thalidomide for Recurrent Bleeding Due to Small-Intestinal Angiodysplasia
Authors: Huimin Chen, Shan Wu, Mingyu Tang, Ran Zhao, Qingwei Zhang, Zihao Dai, Yunjie Gao, Shiming Yang, Zhaoshen Li, Yiqi Du, Aiming Yang, Liang Zhong, Lungen Lu, Leiming Xu, Xizhong Shen, Side Liu, Jie Zhong, Xiaobo Li, Hong Lu, Hua Xiong, Yufeng Shen, Haiying Chen, Shuai Gong, Hanbing Xue, Zhizheng Ge
Journal: New England Journal of Medicine (2023)

Recurrent bleeding from the small intestine accounts for 5 to 10% of cases of gastrointestinal bleeding and remains a therapeutic challenge. Thalidomide has been evaluated for the treatment of recurrent bleeding due to small-intestinal angiodysplasia (SIA), but confirmatory trials are lacking.
Hope, Hype, and Reality of Pulsed Field Ablation for Atrial Fibrillation
Authors: T. Jared Bunch
Journal: New England Journal of Medicine (2023)

Catheter ablation for atrial fibrillation is an increasingly used and effective treatment for arrhythmia.1 However, catheter ablation remains limited on the basis of two broad issues. The first is efficacy rates that remain suboptimal and relatively stagnant despite the introduction of multiple new forms of technology and strategic approaches. Contemporary estimates of success at 1 year after ablation, as defined by the absence of medications, are 67 to 74% for paroxysmal atrial fibrillation2,3 and 43% for persistent and long-standing persistent atrial fibrillation.4 Second, relatively rare risks persist that can result in substantial complications and death. Of these, atrioesophageal fistula is . . .
Association of SARS-CoV-2 Infection during Early Weeks of Gestation with Situs Inversus
Authors: Yanlin Wang, Zhenming Guo, Baoying Ye, Liangjie Liu, Xiao Mao, Yingchun Luo, Shaorong Gao, Guang He, Shan Bian
Journal: New England Journal of Medicine (2023)
Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis
Authors: Hagit Baris Feldman, Chofit Chai Gadot, David Zahler, Adi Mory, Galit Aviram, Emil Elhanan, Gabi Shefer, Ilana Goldiner, Yam Amir, Alina Kurolap, Jacob N. Ablin
Journal: New England Journal of Medicine (2023)

Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium. Each had a homozygous null variant in CORIN, the gene encoding atrial natriuretic peptide (ANP)–converting enzyme. A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP but had elevated levels of B-type natriuretic peptide (BNP) and one of the two protein markers of fibrosis that we tested. These and other findings support the hypothesis that BNP cannot fully compensate for a lack of activation of the ANP pathway and that corin is critical to normal ANP activity, left atrial function, and cardiovascular homeostasis.
Reducing Harm — Having Conversations about Firearm Storage
Authors: Ruth Abaya, Emmy Betz, Carl Kincaid, Sandra McKay, Chana A. Sacks, Joseph Shahoud, Tahmir L. Suters, Darren Taichman, Kendra Van de Water, Rayquan Williams
Journal: New England Journal of Medicine (2023)

In this video from the New England Journal of Medicine, Drs. Emmy Betz (University of Colorado), Ruth Abaya (Children's Hospital of Philadelphia), and Sandra McKay (University of Texas) discuss the importance of clinicians having conversations about firearm safety and storage with patients and families, and they outline high-yield opportunities to have such conversations. The video also shows several different types of gun safety and storage devices.
Encased in Peril
Authors: Gurleen Kaur, Marc S. Sabatine, Inga-Marie Schaefer, Yee-Ping Sun, Joseph Loscalzo
Journal: New England Journal of Medicine (2023)

A 75-year-old man with a history of atrial tachyarrhythmias, tricuspid regurgitation, and pericarditis presented with worsening dyspnea, leg swelling, and abdominal bloating after recent catheter ablation.
First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826
Authors: Bradley J. Monk, Nicoletta Colombo, Krishnansu S. Tewari, Coraline Dubot, M. Valeria Caceres, Kosei Hasegawa, Ronnie Shapira-Frommer, Pamela Salman, Eduardo Yañez, Mahmut Gümüş, Mivael Olivera Hurtado de Mendoza, Vanessa Samouëlian, Vincent Castonguay, Alexander Arkhipov, Cumhur Tekin, Kan Li, Stephen M. Keefe, Domenica Lorusso
Journal: Journal of Clinical Oncology (2023)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The phase III, double-blind KEYNOTE-826 trial of pembrolizumab 200 mg or placebo once every 3 weeks for up to 35 cycles plus platinum-based chemotherapy, with or without bevacizumab, showed statistically significant survival benefits with the addition of pembrolizumab for patients with persistent, recurrent, or metastatic cervical cancer (primary data cutoff: May 3, 2021). This article reports the protocol-specified final overall survival (OS) results tested in the PD-L1 combined positive score (CPS) ≥1, all-comer, and CPS ≥10 populations. At the final data cutoff (October 3, 2022), the median study follow-up duration was 39.1 months (range, 32.1-46.5 months). In the PD-L1 CPS ≥1 (N = 548), all-comer (N = 617), and CPS ≥10 (N = 317) populations, median OS with pembrolizumab–chemotherapy versus placebo–chemotherapy was 28.6 months versus 16.5 months (hazard ratio [HR] for death, 0.60 [95% CI, 0.49 to 0.74]), 26.4 months versus 16.8 months (HR, 0.63 [95% CI, 0.52 to 0.77]), and 29.6 months versus 17.4 months (HR, 0.58 [95% CI, 0.44 to 0.78]), respectively. The incidence of grade ≥3 adverse events was 82.4% with pembrolizumab–chemotherapy and 75.4% with placebo–chemotherapy. These results show that pembrolizumab plus chemotherapy, with or without bevacizumab, continued to provide clinically meaningful improvements in OS for patients with persistent, recurrent, or metastatic cervical cancer.
Influence of Impaired Conduction on Exercise Hemodynamics in Patients With Preserved Ejection Fraction
Authors: Joseph P. Hogarty, Andrea Comella, Shane Nanayakkara, Jeremy William, Dion Stub, Justin A. Mariani, Hitesh C. Patel, Peter M. Kistler, David M. Kaye, Aleksandr Voskoboinik
Journal: JACC Heart Failure (2023)
Echocardiographic Reference Ranges of Global Longitudinal Strain for All Cardiac Chambers Using Guideline-Directed Dedicated Views
Authors: John Nyberg, Even Olav Jakobsen, Andreas Østvik, Espen Holte, Stian Stølen, Lasse Lovstakken, Bjørnar Grenne, Havard Dalen
Journal: JACC. Cardiovascular imaging (2023)

Myocardial deformation by echocardiographic strain imaging is a key measurement in cardiology, providing valuable diagnostic and prognostic information. Reference ranges for strain should be established from large healthy populations with minimal methodologic biases and variability.
Prevalence and Incidence of Atrial Functional Mitral Regurgitation and its Association With Mortality
Authors: Jwan A. Naser, Hector I. Michelena, Patricia A. Pellikka, Christopher G. Scott, Austin M. Kennedy, Grace Lin, Vuyisile T. Nkomo, Sorin V. Pislaru
Journal: JACC. Cardiovascular imaging (2023)
Changes in Preventive Therapies Following Coronary Computed Tomography Angiography vs Invasive Angiography in Nonobstructive CAD
Authors: Nare Torosyan, Brandon Schwartz, Billy Chen, Joseph E. Ebinger, Heidi Gransar, Rebekah Park, Alan Rozanski, C. Noel Bairey Merz, Daniel S. Berman
Journal: JACC. Cardiovascular imaging (2023)
Comprehensive Myocardial Assessment by Computed Tomography
Authors: Hideki Koike, Miho Fukui, Thomas Treibel, Larissa I. Stanberry, Victor Y. Cheng, Maurice Enriquez-Sarano, Stephanie Schmidt, Erik B. Schelbert, Cheng Wang, Atsushi Okada, Asa Phichaphop, Paul Sorajja, Vinayak N. Bapat, Jonathon Leipsic, John R. Lesser, João L. Cavalcante
Journal: JACC. Cardiovascular imaging (2023)
The chemokine CXCL14 is a novel early prognostic biomarker for poor outcome in acetaminophen-induced acute liver failure
Authors: David S. Umbaugh, Nga T. Nguyen, Steven C. Curry, Jody A. Rule, William M. Lee, Anup Ramachandran, Hartmut Jaeschke
Journal: Hepatology (2023)

Background and Aims: Patients with acetaminophen-induced acute liver failure are more likely to die while on the liver transplant waiting list than those with other causes of acute liver failure. Therefore, there is an urgent need for prognostic biomarkers that can predict the need for liver transplantation early after an acetaminophen overdose. Approach and Results: We evaluated the prognostic potential of plasma chemokine C-X-C motif ligand 14 (CXCL14) concentrations in patients with acetaminophen (APAP) overdose (n=50) and found that CXCL14 is significantly higher in nonsurviving patients compared to survivors with acute liver failure ( p &lt; 0.001). Logistic regression and AUROC analyses revealed that CXCL14 outperformed the MELD score, better discriminating between nonsurvivors and survivors. We validated these data in a separate cohort of samples obtained from the Acute Liver Failure Study Group (n = 80), where MELD and CXCL14 had similar AUC (0.778), but CXCL14 demonstrated higher specificity (81.2 vs. 52.6) and positive predictive value (82.4 vs. 65.4) for death or need for liver transplantation. Next, combining the patient cohorts and using a machine learning training/testing scheme to mimic the clinical scenario, we found that CXCL14 outperformed MELD based on AUC (0.821 vs. 0.787); however, combining MELD and CXCL14 yielded the best AUC (0.860). Conclusions: We find in 2 independent cohorts of acetaminophen overdose patients that circulating CXCL14 concentration is a novel early prognostic biomarker for poor outcomes, which may aid in guiding decisions regarding patient management. Moreover, our findings reveal that CXCL14 performs best when measured soon after patient presentation to the clinic, highlighting its importance for early warning of poor prognosis.
Systemic Inflammation With High-Sensitivity C-Reactive Protein and Atherosclerotic Plaque Progression
Authors: Solomon Bienstock, Sang-Eun Lee, Fay Lin, Ron Blankstein, Jonathon Leipsic, Krishna Patel, Jagat Narula, Y.S. Chandrashekhar, Valentin Fuster, Leslee J. Shaw
Journal: JACC. Cardiovascular imaging (2023)
Intrathecal delivery of nanoparticle PARP inhibitor to the cerebrospinal fluid for the treatment of metastatic medulloblastoma
Authors: Minsoo Khang, Ju Hyun Lee, Teresa Lee, Hee-Won Suh, Supum Lee, Alessandra Cavaliere, Amy Rushing, Luiz H. Geraldo, Erika Belitzky, Samantha Rossano, Henk M. de Feyter, Kwangsoo Shin, Anita Huttner, Martine F. Roussel, Jean-Leon Thomas, Richard E. Carson, Bernadette Marquez-Nostra, Ranjit S. Bindra, W. Mark Saltzman
Journal: Science Translational Medicine (2023)

The morbidity associated with pediatric medulloblastoma, in particular in patients who develop leptomeningeal metastases, remains high in the absence of effective therapies. Administration of substances directly into the cerebrospinal fluid (CSF) is one approach to circumvent the blood-brain barrier and focus delivery of drugs to the site of tumor. However, high rates of CSF turnover prevent adequate drug accumulation and lead to rapid systemic clearance and toxicity. Here, we show that PLA-HPG nanoparticles, made with a single-emulsion, solvent evaporation process, can encapsulate talazoparib, a PARP inhibitor (BMN-673). These degradable polymer nanoparticles improve the therapeutic index when delivered intrathecally and lead to sustained drug retention in the tumor as measured with PET imaging and fluorescence microscopy. We demonstrate that administration of these particles into the CSF, alone or in combination with systemically administered temozolomide, is a highly effective therapy for tumor regression and prevention of leptomeningeal spread in xenograft mouse models of medulloblastoma. These results provide a rationale for harnessing nanoparticles for the delivery of drugs limited by brain penetration and therapeutic index and demonstrate important advantages in tolerability and efficacy for encapsulated drugs delivered locoregionally.
Letter to the Editor: Medications promoting abstinence in alcohol-associated cirrhosis
Authors: Alain Braillon, Florian Naudet
Journal: Hepatology (2023)

1Retired senior consultant. 80000 Amiens, France 2Professor in Therapeutics. University of Rennes, CHU Rennes, Inserm, Irset (Institut de recherche en santé, environnement et travail)-UMR_S 1085, CIC 1414 (Centre of Clinical Investigation of Rennes), Rennes, France Correspondence Alain Braillon. Email: [email protected] 488 w. including 5 ref. (limit: 500 words including r no more than no more than 5 references)
Reply: Medications promoting abstinence in alcohol-associated cirrhosis
Authors: Jordi Gratacós-Ginès, Hugo López-Pelayo, Elisa Pose
Journal: Hepatology (2023)

1Liver Unit, Hospital Clínic de Barcelona, Catalunya, Spain 2Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain 3Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain 4Addictions Unit, Department of Psychiatry, Hospital Clínic de Barcelona, Catalunya, Spain 5Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain 6Faculty of Medicine and Health Sciences, University of Barcelona, Catalunya, Spain Correspondence Jordi Gratacós-Ginès, Hospital Clinic de Barcelona, Liver Unit. Email: [email protected]
Shifting the trajectory of therapeutic development for neurological and psychiatric disorders
Authors: Dimitri Krainc, William J. Martin, Bradford Casey, Frances E. Jensen, Sarah Tishkoff, William Z. Potter, Steven E. Hyman
Journal: Science Translational Medicine (2023)

Clinical trials for central nervous system disorders often enroll patients with unrecognized heterogeneous diseases, leading to costly trials that have high failure rates. Here, we discuss the potential of emerging technologies and datasets to elucidate disease mechanisms and identify biomarkers to improve patient stratification and monitoring of disease progression in clinical trials for neuropsychiatric disorders. Greater efforts must be centered on rigorously standardizing data collection and sharing of methods, datasets, and analytical tools across sectors. To address health care disparities in clinical trials, diversity of genetic ancestries and environmental exposures of research participants and associated biological samples must be prioritized.
Fecal microbiota transplantation promotes reduction of antimicrobial resistance by strain replacement
Authors: Michael H. Woodworth, Roth E. Conrad, Marina Haldopoulos, Stephanie M. Pouch, Ahmed Babiker, Aneesh K. Mehta, Kaitlin L. Sitchenko, Charlotte H. Wang, Amanda Strudwick, Jessica M. Ingersoll, Cécile Philippe, Sarah Lohsen, Kumru Kocaman, Blake G. Lindner, Janet K. Hatt, Rheinallt M. Jones, Candace Miller, Andrew S. Neish, Rachel Friedman-Moraco, Geeta Karadkhele, Ken H. Liu, Dean P. Jones, C. Christina Mehta, Thomas R. Ziegler, David S. Weiss, Christian P. Larsen, Konstantinos T. Konstantinidis, Colleen S. Kraft
Journal: Science Translational Medicine (2023)

Multidrug-resistant organism (MDRO) colonization is a fundamental challenge in antimicrobial resistance. Limited studies have shown that fecal microbiota transplantation (FMT) can reduce MDRO colonization, but its mechanisms are poorly understood. We conducted a randomized, controlled trial of FMT for MDRO decolonization in renal transplant recipients called PREMIX (NCT02922816). Eleven participants were enrolled and randomized 1:1 to FMT or an observation period followed by delayed FMT if stool cultures were MDRO positive at day 36. Participants who were MDRO positive after one FMT were treated with a second FMT. At last visit, eight of nine patients who completed all treatments were MDRO culture negative. FMT-treated participants had longer time to recurrent MDRO infection versus PREMIX-eligible controls who were not treated with FMT. Key taxa (
Cold-blooded vertebrates evolved organized germinal center–like structures
Authors: Yasuhiro Shibasaki, Sergei Afanasyev, Alvaro Fernández-Montero, Yang Ding, Shota Watanabe, Fumio Takizawa, Jesús Lamas, Francisco Fontenla-Iglesias, José Manuel Leiro, Aleksei Krasnov, Pierre Boudinot, J. Oriol Sunyer
Journal: Science Immunology (2023)

Germinal centers (GCs) or analogous secondary lymphoid microstructures (SLMs) are thought to have evolved in endothermic species. However, living representatives of their ectothermic ancestors can mount potent secondary antibody responses upon infection or immunization, despite the apparent lack of SLMs in these cold-blooded vertebrates. How and where adaptive immune responses are induced in ectothermic species in the absence of GCs or analogous SLMs remain poorly understood. Here, we infected a teleost fish (trout) with the parasite Ichthyophthirius multifiliis (Ich) and identified the formation of large aggregates of highly proliferating IgM + B cells and CD4 + T cells, contiguous to splenic melanomacrophage centers (MMCs). Most of these MMC-associated lymphoid aggregates (M-LAs) contained numerous antigen (Ag)–specific B cells. Analysis of the IgM heavy chain CDR3 repertoire of microdissected splenic M-LAs and non–M-LA areas revealed that the most frequent B cell clones induced after Ich infection were highly shared only within the M-LAs of infected animals. These M-LAs represented highly polyclonal SLMs in which Ag-specific B cell clonal expansion occurred. M-LA–associated B cells expressed high levels of activation-induced cytidine deaminase and underwent significant apoptosis, and somatic hypermutation of Igμ genes occurred prevalently in these cells. Our findings demonstrate that ectotherms evolved organized SLMs with GC-like roles. Moreover, our results also point to primordially conserved mechanisms by which M-LAs and mammalian polyclonal GCs develop and function.
Targeting a cell-specific microRNA repressor of CXCR4 ameliorates atherosclerosis in mice
Authors: Ismail Cimen, Lucia Natarelli, Zahra Abedi Kichi, James M. Henderson, Floriana M. Farina, Eva Briem, Maria Aslani, Remco T.A. Megens, Yvonne Jansen, Elizabeth Mann-Fallenbuchel, Selin Gencer, Johan Duchêne, Maliheh Nazari-Jahantigh, Emiel P.C. van der Vorst, Wolfgang Enard, Yvonne Döring, Andreas Schober, Donato Santovito, Christian Weber
Journal: Science Translational Medicine (2023)

The CXC chemokine receptor 4 (CXCR4) in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) is crucial for vascular integrity. The atheroprotective functions of CXCR4 in vascular cells may be counteracted by atherogenic functions in other nonvascular cell types. Thus, strategies for cell-specifically augmenting CXCR4 function in vascular cells are crucial if this receptor is to be useful as a therapeutic target in treating atherosclerosis and other vascular disorders. Here, we identified miR-206-3p as a vascular-specific CXCR4 repressor and exploited a target-site blocker (CXCR4-TSB) that disrupted the interaction of miR-206-3p with CXCR4 in vitro and in vivo. In vitro, CXCR4-TSB enhanced CXCR4 expression in human and murine ECs and VSMCs to modulate cell viability, proliferation, and migration. Systemic administration of CXCR4-TSB in Apoe -deficient mice enhanced Cxcr4 expression in ECs and VSMCs in the walls of blood vessels, reduced vascular permeability and monocyte adhesion to endothelium, and attenuated the development of diet-induced atherosclerosis. CXCR4-TSB also increased CXCR4 expression in B cells, corroborating its atheroprotective role in this cell type. Analyses of human atherosclerotic plaque specimens revealed a decrease in CXCR4 and an increase in miR-206-3p expression in advanced compared with early lesions, supporting a role for the miR-206-3p–CXCR4 interaction in human disease. Disrupting the miR-206-3p–CXCR4 interaction in a cell-specific manner with target-site blockers is a potential therapeutic approach that could be used to treat atherosclerosis and other vascular diseases.
Tumor-specific GPX4 degradation enhances ferroptosis-initiated antitumor immune response in mouse models of pancreatic cancer
Authors: Jingbo Li, Jiao Liu, Zhuan Zhou, Runliu Wu, Xin Chen, Chunhua Yu, Brent Stockwell, Guido Kroemer, Rui Kang, Daolin Tang
Journal: Science Translational Medicine (2023)

Lipid peroxidation-dependent ferroptosis has become an emerging strategy for tumor therapy. However, current strategies not only selectively induce ferroptosis in malignant cells but also trigger ferroptosis in immune cells simultaneously, which can compromise anti-tumor immunity. Here, we used In-Cell Western assays combined with an unbiased drug screening to identify the compound N6F11 as a ferroptosis inducer that triggered the degradation of glutathione peroxidase 4 (GPX4), a key ferroptosis repressor, specifically in cancer cells. N6F11 did not cause the degradation of GPX4 in immune cells, including dendritic, T, natural killer, and neutrophil cells. Mechanistically, N6F11 bound to the RING domain of E3 ubiquitin ligase tripartite motif containing 25 (TRIM25) in cancer cells to trigger TRIM25-mediated K48-linked ubiquitination of GPX4, resulting in its proteasomal degradation. Functionally, N6F11 treatment caused ferroptotic cancer cell death that initiated HMGB1-dependent antitumor immunity mediated by CD8+ T cells. N6F11 also sensitized immune checkpoint blockade that targeted CD274/PD-L1 in advanced cancer models, including genetically engineered mouse models of pancreatic cancer driven by KRAS and TP53 mutations. These findings may establish a safe and efficient strategy to boost ferroptosis-driven antitumor immunity.
The SGLT2 inhibitor dapagliflozin improves kidney function in glycogen storage disease XI
Authors: Francesco Trepiccione, Anna Iervolino, Mariavittoria D’Acierno, Sabrina Siccardi, Vincenzo Costanzo, Donato Sardella, Luigi R. De La Motte, Luciano D’Apolito, Antonio Miele, Alessandra F. Perna, Giovanna Capolongo, Miriam Zacchia, Sebastian Frische, Rikke Nielsen, Leopoldo Staiano, Irene Sambri, Rossella De Cegli, Robert Unwin, Dominique Eladari, Giovambattista Capasso
Journal: Science Translational Medicine (2023)

Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the SLC2A2 gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS, SLC2A2 expression was ablated in mouse kidney and HK-2 proximal tubule cells. GLUT2Pax8Cre+ mice developed time-dependent glycogen accumulation in proximal tubule cells and recapitulated the renal Fanconi phenotype seen in patients. In vitro suppression of GLUT2 impaired lysosomal autophagy as shown by transcriptomic and biochemical analysis. However, this effect was reversed by exposure to a low glucose concentration, suggesting that GLUT2 facilitates the homeostasis of key cellular pathways in proximal tubule cells by preventing glucose toxicity. To investigate whether targeting proximal tubule glucose influx can limit glycogen accumulation and correct symptoms in vivo, we treated mice with the selective SGLT2 inhibitor dapagliflozin. Dapagliflozin reduced glycogen accumulation and improved metabolic acidosis and phosphaturia in the animals by normalizing the expression of Napi2a and NHE3 transporters. In addition, in a patient with FBS, dapagliflozin was safe, improved serum potassium and phosphate concentrations, and reduced glycogen content in urinary shed cells. Overall, this study provides proof of concept for dapagliflozin as a potentially suitable therapy for FBS.